Partial characterization and assignment of the gene for protoporphyrinogen oxidase and variegate porphyria to human chromosome 1q23.

Protoporphyrinogen oxidase (PPO) catalyses the conversion of protoporphyrinogen IX to protoporphyrin IX. Variegate porophyria (VP), a low-penetrant, autosomal dominate disorder characterized clinically by skin lesions and neurovisceral attacks, is caused by partial deficiency of this enzyme. Linkage between VP and the alpha-1-antitrypsin gene on chromosome 14 has been reported in VP families from South Africa, where the condition occurs at high frequency due to a founder effect. We have cloned a 4.5 kb genomic DNA fragment containing the entire coding sequence for human PPO. This clone has been used to localize the human PPO gene to chromosome 1q23 by fluorescence in situ hybridization analysis. The VP gene was mapped by linkage analysis, using microsatellite markers spanning the region 1q21-q25.1, in seven British VP families. Multipoint analysis between VP, SPTA1, APOA2 and D1S194 gave the maximum LOD score of 6.62 at APOA2, which has been physically mapped to 1q21-q23. Evidence for significant linkage between VP and markers in the alpha-1-antitrypsin region of chromosome 14 was not obtained. Our results assign the genes for PPO and VP to the same region chromosome 1, indicate that the PPO and VP loci are likely to be the same, and provide evidence against locus heterogeneity in VP.